An estimated 21 million adults in the United States alone live with osteoarthritis, one of the most common types of arthritis. Osteoarthritis, also called degenerative joint disease, is caused by the breakdown of cartilage, the connective tissue that cushions the ends of bones within the joint. Osteoarthritis is characterized by pain, joint damage, and limited joint motion. This disease generally occurs late in a patient's life, and most commonly affects the hands and larger weight-bearing joints. Additionally, age, gender (females), and obesity are risk factors for this disease.
Researchers have found that in degenerating cartilage, pro-inflammatory cytokines, such as IL-1β and TNFα, are associated with an increased degradation of cartilage matrix (Sandy et al., Biochem. J., 335:59-66 (1998); Seguin et al., J. Cell Physiol., 197:356-369 (2003)). These events are also correlated with the reduction in the cartilage matrix gene expression and syntheses in vitro (Gouze et al., FEBS Letters, 510:166-170 (2002); Shikhman et al., J. Immunol., 166:5155-5160 (2001)).
The amino monosaccharide glucosamine, naturally occurring in cartilage and connective tissues, contributes to maintaining strength, flexibility, and elasticity of these tissues. Glucosamine is a precursor to a glycosaminglycan molecule, which is used in the formation and repair of cartilage. In vivo, glucosamine is typically converted to N-acetyl glucosamine. In recent years, glucosamine has been used widely to treat the symptoms of osteoarthritis in human and animal models, serving in an anti-inflammatory capacity in reducing joint swelling and pain levels comparable with that observed with non-steroidal anti-inflammatory drugs (NSAIDs) (Lopes, Curr. Med. Res. Opin., 8:145-149 (1982); Muller-Fassbender et al., Osteoarthritis Cartilage, 2:61-69 (1994); Ruane et al., Br. J. Community Nurs., 7:148-152 (2002)). Some have also concluded that glucosamine counteracts the degradative effects that IL-1β has on proteoglycan syntheses (Sandy et al., Biochem J., 335:59-66 (1998); Gouze et al., FEBS Letters, 510:166-170 (2002)), as glucosamine reduces nitric oxide production induced by IL-1β and TNFα (Shikhman et al., J. Immunol., 166:5155-5160 (2001)) and suppresses the syntheses of cyclooxygenase-2 (COX-2) by human chondrocytes in response to IL-1β (Largo et al., Osteoarthritis Cartilage, 11:290-298 (2003)). Thus, glucosamine may also serve in the management of diseases associated with degeneration of cartilage tissues, such as osteoarthritis.
The use of glucosamine gained popularity after being featured in the book, The Arthritis Cure by Jason Theodasakis, MD, et al. (St. Martin's Press. New York, N.Y. 1997). Between 1997 and 2002, the annual market growth rate of glucosamine has exceeded 36.4% (Chemical Market Reporter, vol. 264(1), Jul. 14, 2003). Currently, glucosamine and its metabolites are not classified as drugs, but as nutraceutical/dietary supplements under United States Food and Drug Administration's Dietary Supplement Health and Education Act of 1994 (DSHEA). Oral dosage formulations of N-acetyl-D-glucosamine and its parent compound glucosamine in salt form (sulfate, hydrochloride etc.) are commercially available nutraceuticals, and are commonly administered in conjunction with chondroitin sulfate, also a readily available nutraceutical. Glucosamine and chondroitin have been reported effective in the oral treatment of osteoarthritis but have not undergone the rigorous studies needed for FDA approval as pharmaceuticals. (Theodasakis et al., The Arthritis Cure, 1st Edition, St. Martin's Press. New York, N.Y. 1997; McAlindon et al., JAMA, 283:469-1475 (2000)). The National Institutes of Health (Bethesda, Md., USA) has an ongoing multi-center study-GAIT (Glucosamine/Chondroitin Arthritis Intervention Trial) that is currently evaluating the efficacy of orally administered glucosamine and chondroitin oral supplements (Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), National Center for Complementary and Alternative Medicine (NCCAM), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) September 1999).
While oral administration is the most widely recognized method of administering glucosamine, the effectiveness of glucosamine administered subcutaneously has also been studied. For example, there currently exists an FDA approved therapy, SYNVISC (Genzyme Corp., Naarden, the Netherlands) for the local treatment of pain associated with osteoarthritis of the knee. The treatment includes injection of a solution including sodium hyaluronate (a glycosaminoglycan) at the affected joint. However, SYNVISC is currently approved only for treatment of the knee.
Non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing inflammation, and are often used to treat the symptoms of osteoarthritis. However, NSAIDs may have undesirable side effects. Efforts have been made to improve the pharmaceutical properties of NSAIDs, such as permeability, solubility, and stability, by creating NSAID “prodrugs.” A prodrug is a drug precursor. The term “prodrug” has been used to describe a compound that is composed of one active drug compound and a second, non-active compound. The prodrug is not active as a pharmacological agent until it undergoes a chemical conversion, e.g., via metabolic processes after administration to a patient. Once converted, the prodrug provides the active pharmaceutical agent and the nonactive compound that is typically inert after conversion.
The prodrug concept was initially articulated by Albert (Nature, 182(4633):421-423 (1958)). The original objectives of prodrug synthesis and development were to improve drug stability and to target drug delivery for drugs administered orally and intravenously. Stability is significant to drug activity, and for water and enzyme labile drugs, stability is typically achieved by protecting the drug from chemical hydrolysis and enzyme degradation subsequent to drug administration. Targeted delivery for prodrugs is based on enhancing drug solubility and permeability, and is particularly useful in drug administration associated with lipid membranes in order to penetrate the very hydrophobic blood brain barrier.
The most common form of prodrug utilizes an ester linkage formed synthetically through reaction of a carboxylic acid with an alcohol or phenol to modify the parent drug's in vivo metabolic fate. In addition to affecting the metabolism of the parent drug, the ester prodrug may possess other advantages, such as reduced side effects. For example gastric distress may be reduced if the nonsteroidal anti-inflammatory drug (NSAID) were formulated as a prodrug, as compared with the NSAID administered alone. Positive characteristics associated with prodrug usage include, for example, the presence of stable covalent ester linkage, less intrinsic activity compared to the parent drug, lower toxicity, and better release kinetics at the binding site to ensure effective drug levels.
“Mutual prodrugs,” representing a variation of a prodrug, can be described as the conjugation of two drugs having different pharmacological activities. The concept arises from the practice of clinically co-administering two drugs in order to enhance pharmacological activity or prevent clinical side effects (U.S. Pat. No. 4,278,679). Mutual prodrugs are synthesized toward a pharmacological objective of improving each drug's efficacy, optimizing delivery, and lowering toxicities.
In a mutual prodrug, each component drug functions as the “pro” portion with respect to the other. Like a prodrug, a mutual prodrug is converted into the component active drugs within the body through enzymatic and/or non-enzymatic reactions. Mutual prodrugs can be classified as, for example, carrier-linked prodrugs, bio-precursor prodrugs, or chemical activation prodrugs, depending upon their constituents and composition (Albert, Nature, 182(4633):421-423 (1958); Rao, H Surya Prakash (available on the internet at ias.ac.in/resonance/Feb2003/pdf/Feb2003p19-27.pdf), Capping Drugs: Development of Prodrugs.k February, 2003). At the site of action, the side effects of the original drug would be masked allowing the drug to work more effectively (Albert, Nature, 182(4633):421-423 (1958)). Mutual prodrugs are typically similar to single active agent prodrugs in regard to pharmaceutical and pharmacological activities, such as absorption, disposition, metabolism, and excretion. The objective of a mutual prodrug is for both active drugs reaching their respective active sites, to provide the desired pharmacological effects while minimizing adverse metabolic and/or toxicological events.
For many years before the terms “prodrug” and “mutual prodrug” were coined in the research domain, combination drugs have been administered to patients as therapeutic agents (Singh et al., Indian J. Pharm. Sci, 56(3):69-79 (1994)), for example in relation to the production of sulphasalazine, representing modern advances in antibiotic prodrugs. Essentially, this has led to combinations of β-lactam antibiotics and their potentiating agents to produce, for example ampicillin-mecillinam and ampicillan-sulbactam to form sultamicillin, and Dual Action Cephalosporins as well as other agents not typically referred to as mutual prodrugs (Singh et al., Indian J. Pharm. Sci, 56(3):69-79 (1994))
One example of a mutual prodrug is estramustine sodium phosphate (EMCYT, Pharmacia, La Roche) developed in the early 1970's as an anti-neoplastic agent that shows certain mutual prodrug characteristics (Wang et al., Biochem. Pharmacol., 55(9):1427-33 (1998); Sheridan et al., Cancer Surv., 11:239-254 (1991); Ohsawa et al., Gan To Kagaku Ryoho., April; 15(4 Pt 2-1):1065-71 (1998); Forsgren et al., Urol Nephrol Suppl., 107:56-58 (1988)). Estramustine is typically used in the treatment of metastatic carcinoma of the prostate. Estramustine is selectively taken up into estrogen receptor positive cells and then, as shown in FIG. 1, the urethane linkage is hydrolyzed to give 17-alphaestradiol, which slows prostate cell growth, and nornitrogen mustard as a weak alkylating agent.
Prodrug research has continued, as exemplified by the synthesis of 5-fluorouracil/cytarabine mutual prodrugs designed to reduce the resistance mechanisms at work in the delivery of single nucleoside drugs (Menger et al., J. Org. Chem., 62:9083-9088 (1997)). Researchers such as Bhosale and co-workers have made attempts to produce mutual prodrugs of ibuprofen/paracetamol and ibuprofen/salicylaminde. The goal of this work was to produce prodrugs of NSAIDS to reduce the associated side effects (Bhosale et al., Indian J. Pharm. Sci., 66(2):158-163 (2003)). Their approach was unique from the perspective of producing mutual prodrugs vis-à-vis physicochemical modifications towards simplistic NSAID delivery, much like sulphasalazine, currently used more so as a ulcerative colitis therapeutic consisting of sulphapyridine and 5-aminosaicylic acid covalently bound via an azo bond (Klotz et al., Adv. Drug Deliv. Rev., 57(2):267-279 (2005); Lim et al., Rev. Gastroenterol. Disord., 4(3):104-117 (2004); Baker et al., Rev. Gastroenterol. Disord., 4(2):86-91 (2004); and Diculescu et al., Rom. J. Gastroenterol., 12(4):283-286 (2003). Structures of Sulphasalazine (FIG. 2A), 5-Fluorouracil/Cytarabine (FIG. 2B), Ibuprofen/Paracetamol (FIG. 2C), and Ibuprofen/Salicylamide (FIG. 2D) are provided in FIG. 2.